db (diabetes) in the mouse and fa (fatty), its likely homolog in the rat, are spontaneous recessive mutations which result in an obese phenotype. Obese rodents homozygous for db or fa, show susceptibility or resistance to non insulin-dependent diabetes mellitus (NIDDM) which depends upon the inbred strain backgrounds on which these obesity mutations are maintained. This finding suggests that in the homozygous recessive state, obesity genes provide a context in which strain-specific gene products act as modifiers of the diabetic phenotype. The main objectives of this proposal are to define the molecular mechanisms involved in the development of obesity and NIDDM. The specific aims and methods include: isolating and subcloning cDNA fragments that are differentially expressed in relevant tissues of homozygous db and fa animals and their wild type littermates using the cDNA differential display and molecular cloning techniques; sequencing the cDNA fragments to determine if they are encoded by known or novel genes; identifying the chromosomal location of these genes by genomic mapping using polymorphic molecular markers on DNA panels from interspecific and intersubspecific backcrosses and intercrosses; isolating full-length cDNA clones by screening relevant cDNA libraries; determining spatial-temporal gene expression patterns of the cDNAs by Northern blot hybridization, in situ hybridization and immunohistochemistry to embryonic and adult tissue sections; and assessing the relevance of these genes to human obesity and NIDDM by linkage analyses.